Multidrug resistance (MDR) is the major cause of cancer chemotherapy failure, and remains an unsolved problem in clinic. The most established mechanism for MDR is the overexpression of ATP-binding cassette (ABC) family membrane transporters. Up to now, ABC transporters have 49 members, among which ABCB1, ABCG2 and ABCCs are known as the most important members that result in MDR in cancer cells.
ABCB1, also known as glycoprotein P (P-gp) encoded by MDR1 gene, was the first cloned human ABC transporter that can transport a large number of compounds including most chemotherapeutic drugs such as taxanes (e.g. paclitaxel (PTX) and docetaxel) and anthracyclines (e.g. doxorubicin (DOX) and mitoxantrone). In cancerous tissue, the expression of P-gp is usually highest in tumors that are derived from tissues that normally express P-gp, such as epithelial cells of the colon, kidney, adrenal, pancreas, and liver, resulting in the potential for resistance to some cytotoxic agents. Developing inhibitors that either down-regulate the expression of ABC proteins or inhibit the efflux function of ABC transporters would have potential clinical benefit as a “combination therapy strategy”. However, the first, second and third generations of ABC modulators such as quinine, verapamil, cyclosporine-A, tariquitor, PSC 833, LY335979, and GF120918 required high doses to reverse MDR and were associated with adverse effects. These limitations have spurred efforts to search for new, more effective compounds from natural products with low toxicity and fewer side effects.